Mixed Phosphonate Research Articles

Strategically Modified Ligand Incorporating Mixed Phosphonate and Carboxylate Groups to Enhance Performance in All‐Iron Redox Flow Batteries

AbstractIron redox flow batteries (Fe‐RFBs) hold significant promise for achieving cost‐effectiveness and utilizing abundant materials for stationary energy storage applications. Here, a design of a novel Fe complex utilizing a nitrogenous phosphonate/carboxylate mixed ligand, N,N‐Bis(phosphonomethyl)glycine (BMPG), is presented to achieve high performance Fe anolyte. Compared to its all‐phosphonate form, nitrilotri(methylphosphonic acid) (NTMPA), the new complex Fe(BPMG)2 demonstrates a negatively shifted redox potential, resulting in ≈0.07 V (≈10%) increase in battery output voltage. Full battery testing paired with ferrocyanide catholyte demonstrates stable cycling (capacity degradation <0.0001%/cycle) over 730 consecutive charge/discharge cycles with Coulombic Efficiency of 100% at a current density of 20 mA cm−2 under near neutral pH (≈8). Of particular interest, density functional theory (DFT) studies and operando Raman measurements provide strong evidence supporting a molecular structure in BPMG, which reveals the mixed phosphonate/carboxylate groups in BPMG maintain the octahedral coordination of the Fe ion center with phosphonates exclusively, while leaving the carboxylate unbound for both Fe(II) and Fe(III) complexes. This structural similarity between BPMG‐based Fe(II) and Fe(III) complexes effectively mitigates the slow redox reaction kinetics observed in Fe(NTMPA)2 anolyte, where significant ligand reorientation occurs between Fe(II) and Fe(III) complexes.

Synthesis of Mixed Phosphonate Esters and Amino Acid-Based Phosphonamidates, and Their Screening as Herbicides.

While organophosphorus chemistry is gaining attention in a variety of fields, the synthesis of the phosphorus derivatives of amino acids remains a challenging task. Previously reported methods require the deprotonation of the nucleophile, complex reagents or hydrolysis of the phosphonate ester. In this paper, we demonstrate how to avoid these issues by employing phosphonylaminium salts for the synthesis of novel mixed n-alkylphosphonate diesters or amino acid-derived n-alkylphosphonamidates. We successfully applied this methodology for the synthesis of novel N-acyl homoserine lactone analogues with varying alkyl chains and ester groups in the phosphorus moiety. Finally, we developed a rapid, quantitative and high-throughput bioassay to screen a selection of these compounds for their herbicidal activity. Together, these results will aid future research in phosphorus chemistry, agrochemistry and the synthesis of bioactive targets.

Peptide mixed phosphonates for covalent complex formation with thioesterases in nonribosomal peptide synthetases.

Natural macrocyclic peptides derived from microorganisms are medicinal resources that are important for the development of new therapeutic agents. Most of these molecules are biosynthesized by a nonribosomal peptide synthetase (NRPS). The thioesterase (TE) domain in NRPS is responsible for the macrocyclization of mature linear peptide thioesters in a final biosynthetic step. NRPS-TEs can cyclize synthetic linear peptide analogs and can be utilized as biocatalysts for the preparation of natural product derivatives. Although the structures and enzymatic activities of TEs have been investigated, the substrate recognition and substrate-TE interaction during the macrocyclization step are still unknown. To understand the TE-mediated macrocyclization, here we report the development of a substrate-based analog with mixed phosphonate warheads, which can react irreversibly with the Ser residue at the active site of TE. We have demonstrated that the tyrocidine A linear peptide (TLP) with a p-nitrophenyl phosphonate (PNP) enables efficient complex formation with tyrocidine synthetase C (TycC)-TE containing tyrocidine synthetase.

Structural variability of pendant groups within the interlayer region of zirconium arene-phosph(on)ates: chemical and structural characterization of oxy- and methyl-linked 2-naphthyl phosphonates, and mixed oxy-linked derivatives.

Several new zirconium phosphonates incorporating the naphthalene ring and having the general formula Zr(O3PR)1(O3PR')1 [R and R' = -CH2C10H7, -OC10H7, -CH3, -OC2H5, -OH] have been synthesized. These materials were chemically characterized using thermal gravimetric analysis (percentage of organic content), infrared spectroscopy (presence of the desired organic functional groups), and solid-state 31P NMR (phosphorus environments), while the structural parameters were determined using X-ray powder diffraction (interlayer d spacings). The two new zirconium bis(phosphonates), Zr(O3PC10H7)2 and Zr(O3PCH2C10H7)2, were found to have d spacings of 19.6 and 20.0 Å, respectively. Three of the four zirconium mixed phosphonates examined are found to be single-phase structures with random mixtures of the organic moieties within the interlayer, and possess d spacings (14.3, 15.3, and 16.1 Å) that are between those of the two parent zirconium bis(phosphonates). The fourth is found to be a staged or segregated structure and possesses a d spacing that is approximately a sum of the two parent zirconium bis(phosphonates), with a d spacing of 28.2 Å. Solid-state 31P NMR of Zr(O3PCH2C10H7)2 revealed the presence of two isotropic resonances, which is interpreted in terms of two distinct, "locked-in" conformations of the -CH2C10H7 group. The experimental d spacings of the zirconium bis(phosphonates) correlate well with a simple predictive model based on the effective length and predominant conformation of the organic functional group.

Cover Feature: Stability and Efficiency of Mixed Aryl Phosphonate Prodrugs (ChemMedChem 17/2019)

Cover Feature: Stability and Efficiency of Mixed Aryl Phosphonate Prodrugs (ChemMedChem 17/2019)

Synthesis, pharmacological evaluation, and mechanistic study of adefovir mixed phosphonate derivatives bearing cholic acid and l-amino acid moieties for the treatment of HBV

The deficiency of nucleos(t)ide analogues (NAs) as anti-hepatitis B virus (HBV) drugs in clinical use is attributable to their insufficient enrichment in liver and non-target organ toxicity. We aimed to develop potent anti-HBV adefovir derivatives with hepatotrophic properties and reduced nephrotoxicity. A series of adefovir mono l-amino acids, mono cholic acid-drug conjugates were designed and synthesized, and their antiviral activity and uptake in rat primary hepatocytes and Na+-dependent taurocholate co-transporting polypeptide (NTCP)-HEK293 cells were evaluated. We isolated compound 6c as the optimal molecular candidate, with the highest antiviral activity (EC50 0.42 μmol/L, SI 1063.07) and highest cellular uptake in primary hepatocytes and NTCP-HEK293 cells. In-depth mechanistic studies demonstrated that 6c exhibited a lower toxicity in HK-2 cells when compared to adefovir dipivoxil (ADV). This is because 6c cannot be transported by the human renal organic anion transporter 1 (hOAT1). Furthermore, pharmacokinetic characterization and tissue distribution of 6c indicates it has favorable druggability and pharmacokinetic properties. Further docking studies suggested compounds with ursodeoxycholic acid and l-amino acid groups are better at binding to NTCP due to their hydrophilic properties, indicating that 6c is a potential candidate as an anti-HBV therapy and therefore merits further investigation.

New Strategies for Activation of Phosphonates/Phosphates to Forge Functional Phosphorus Compounds

Organophosphonate analogues are important structural motifs that are present in bioactive natural products, pharmaceuticals, and agrochemicals. Because they are useful in a broad range of applications, much effort has focused on developing efficient synthetic methods that enable access to organophosphonates and their derivatives. However, currently available synthetic procedures rely on harsh reaction conditions and are limited to a narrow substrate scope. Our lab has recently made important advances in leveraging inert phosphonates/phosphates into functional phosphorus compounds such as mixed phosphonates, phosphates, and mixed aryl phosphate derivatives. Presented herein is an overview of recent achievements in the synthesis of phosphonate/phosphate derivatives and a summary of our recent accomplishments in Tf2O-promoted activating strategy of phosphonate analogues.1 Introduction2 Direct Activating Strategy of Phosphonate Analogues3 Late-stage Phosphonylation of Natural Compounds4 Potential Applications5 Summary

Martín Fañanás‐Mastral

Martín Fañanás‐Mastral

Chemoselective Activation of Diethyl Phosphonates: Modular Synthesis of Biologically Relevant Phosphonylated Scaffolds.

Phosphonates have garnered considerable attention for years owing to both their singular biological properties and their synthetic potential. State‐of‐the‐art methods for the preparation of mixed phosphonates, phosphonamidates, phosphonothioates, and phosphinates rely on harsh and poorly selective reaction conditions. We report herein a mild method for the modular preparation of phosphonylated derivatives, several of which exhibit interesting biological activities, that is based on chemoselective activation with triflic anhydride. This procedure enables flexible and even iterative substitution with a broad range of O, S, N, and C nucleophiles.

Direct Aryloxylation/Alkyloxylation of Dialkyl Phosphonates for the Synthesis of Mixed Phosphonates

A strategy for the direct functionalization strategy of inertial dialkyl phosphonates with hydroxy compounds to afford diverse mixed phosphonates with good yields and functional-group tolerance has been developed. Mechanistic investigations involving both NMR studies and DFT studies suggest that an unprecedented highly reactive PV species (phosphoryl pyridin-1-ium salt), a key intermediate for this new synthetic transformation, is generated in situ from dialkyl phosphonate in the presence of Tf2 O/pyridine.

Direct Aryloxylation/Alkyloxylation of Dialkyl Phosphonates for the Synthesis of Mixed Phosphonates

AbstractA strategy for the direct functionalization strategy of inertial dialkyl phosphonates with hydroxy compounds to afford diverse mixed phosphonates with good yields and functional‐group tolerance has been developed. Mechanistic investigations involving both NMR studies and DFT studies suggest that an unprecedented highly reactive PV species (phosphoryl pyridin‐1‐ium salt), a key intermediate for this new synthetic transformation, is generated in situ from dialkyl phosphonate in the presence of Tf2O/pyridine.

ChemInform Abstract: Synthesis, anti‐HBV Activity and Renal Cell Toxicity Evaluation of Mixed Phosphonate Prodrugs of Adefovir.

AbstractA series of phosphonate ester prodrugs (I) of adefovir incorporating L‐amino (thio)acid and non‐steroidal anti‐inflammatory drug (NSAID) moieties is synthesized and evaluated for their anti‐HBV and renal cell toxicity in HepG2 2.2.15 and HK‐2 cells, respectively.

A route to functionalised pores in coordination polymers via mixed phosphonate and amino-triazole linkers

The ability to control size, shape and functionality of pores in materials is of fundamental importance to understanding sorption (host–guest) phenomena. We present a coordination polymer compound with narrow pores lined by free amine functionalities. Cu(aminotriazole)(1,4-dihydrogenphosphonate)hydrate, 1, forms a pillared layered structure where alternating pillaring units are replaced by the N-heterocycle to generate the pores. Single-crystal and powder X-ray diffraction data are presented as well as the thermogravimetric analysis and CO2, N2 and H2 gas sorption analyses.

NCN‐Chelated Organoantimony(III) and Organobismuth(III) Phosphonates: Syntheses and Structures

AbstractThe reactions of the organoantimony and organobismuthoxides [LSbO]2 (1) and [LBiO]2 (2), where L = [2,6‐(Me2NCH2)2C6H3]–, with selected organophosphonic acids in a 1:4 molar ratio gave molecular organoantimony and organobismuth phosphonates LM[OP(R)(O)(OH)]2 [M = Sb, R = Et (3), Ph (4), tBu (5); M = Bi, R = tBu (8)]. Similarly, the reactions of 1 and 2 with tBuP(O)(OH)2 in a 1:2 molar ratio resulted in LM[O2P(tBu)(O)] [M = Sb (6), M = Bi (9)]. Reactions of 6 and 9 with EtP(O)(OH)2 yielded mixed phosphonates LM[OP(Et)(O)(OH)][OP(tBu)(O)(OH)] [M = Sb (7), M = Bi (10)]. All compounds were characterized by elemental analysis, ESI mass spectrometry, 1H, 13C and 31P NMR spectroscopy and IR spectroscopy. Molecular structures of compounds 4, 5, 8 and 9 were determined by using X‐ray single‐crystal diffraction in the solid state. Secondary phosphonates 4, 5 and 8 form weakly bonded dimeric units through hydrogen bridges of the type PO–H···O=P. On the other hand, compound 9 is trimeric in the solid state with the central 12‐membered ring formed by three LBi[O2P(tBu)(O)] building blocks through intermolecular Bi···O=P contacts.

Zirconium Arene-Phosphonates: Chemical and Structural Characterization of 2-Naphthyl- and 2-Anthracenylphosphonate Systems

Several new zirconium phosphonates incorporating naphthalene and anthracene ring systems and having the general formula Zr(O3PR)1(O3PR')1 [R and R' = -C10H7, -C14H9, -OC4H9, and -OC2H5] have been synthesized. These compounds were chemically characterized using thermal gravimetric analysis (percentage of organic content), infrared spectroscopy (presence of the desired organic functional groups), and solid-state 31P NMR (phosphorus environments), while the structural parameters were determined using X-ray powder diffraction (interlayer d spacings). The d spacings of the zirconium bis(phosphonates) correlate well with a simple predictive model based on the effective length of the organic functional group. The zirconium mixed phosphonates examined are single-phase structures with random mixtures of the organic moieties within the interlayer and possess d spacings that are between those of the two parent zirconium bis(phosphonates).

Efficient Synthesis of Mixed Phosphonates by the Fragmentation‐Related Phosphorylation of Alcohols Applying a 2‐phosphabicyclo[2.2.2]octa‐5,7‐Diene 2‐Oxide Precursor

The photochemically induced phosphonylation of C1–C4 alcohols by the fragmentation of a P‐ethoxy 2‐phosphabicyclo[2.2.2]octa‐5,7‐diene 2‐oxide (1) yielded the phosphonates (3) with two different alkoxy group efficiently, without the slightest extent of transesterification.

New Mixed Phosphonate Esters by Transesterification of Pinacol Phosphonates and Their Use in Aldehyde and Ketone Coupling Reactions with Nonstabilized Phosphonates.

AbstractFor Abstract see ChemInform Abstract in Full Text.

New mixed phosphonate esters by transesterification of pinacol phosphonates and their use in aldehyde and ketone coupling reactions with nonstabilized phosphonates.

Alkylpinacol phosphonates were prepared by rhodium-catalyzed olefin hydrophosphorylation, and attempted alpha-deprotonation of the pinacol derived alkyl phosphonates resulted in ring cleavage. The propensity of the alkylpinacol phosphonates to undergo ring opening was exploited to prepare phosphonic acid monomethyl esters in high yield by transesterification in acidulated methanol. Esterification and alkylation with aldehydes or ketones gave beta-hydroxy mixed phosphonate esters. tert-Butyl and benzylic phosphonate ester protective groups were introduced to improve the efficiency and functional group compatibility of beta-hydroxy phosphonate saponification. The beta-hydroxy phosphonic acid monomethyl esters were dehydrated with diisopropylcarbodiimide, which gave oxaphosphetane intermediates that collapse to an olefin. The overall reaction sequence complements the arsenal of Horner-Wadsworth-Emmons-type coupling reactions.

Synthesis and stereochemical elucidation of a 14-membered ring phosphonate.

[structure: see text]. We report the synthesis and stereochemical elucidation of a 14-membered ring phosphonate. The key step in the synthesis of the macrolide phosphonate was the cyclization of the acyclic precursor using the Mitsunobu reaction, a mild reaction for the preparation of mixed phosphonates.

Synthesis, Characterization, and Interlayer Distance Study of Zirconium Phosphonates with Stoichiometric Variation of Methyl and p-Aminobenzyl Pendant Groups

A new class of layered zirconium mixed phosphonates, zirconium (p-aminobenzyl)phosphonate methylphosphonate, Zr(O3PCH2C6H4NH2)x(O3PCH3)2-x [abbreviated as Zr(pab)x(me)2-x], and its intercalated hydrochloride form, Zr(O3PCH2C6H4NH3Cl)x(O3PCH3)2-x [Zr(pabHCl)x(me)2-x], in a number of stoichiometric pendant group ratios, have been synthesized and characterized. For these materials, thermogravimetric analysis was able to identify and quantify, when present, loss of surface-adsorbed water, HCl units, methyl and p-aminobenzyl groups. 31P NMR indicated evidence of two types of phosphorus environments that tracked the stoichiometry but behaved differently in chemical shift variation (6.7−8.5 and 2.2−8.0 ppm). FT-IR measurements quantitatively accounted for relative mole fraction as the pendant group ratio was varied. Interlayer spacing measurements as a function of the stoichiometric ratio were carried out by XRD and corroborated by molecular mechanics calculations. The calculations show that interlayer pendant g...